The utility of bone marrow transplantation for childhood leukemia in patients unable to achieve a remission prior to transplant is controversial. To address this issue, we analyzed a subset of patients with advanced leukemia entered on prospective transplant trials at our hospital. Fifty-eight patients with ALL or AML (age 1-19) were identified. They had failed standard chemotherapy and were in relapse (22 in 1st, 27 in 2nd, three in 3rd, and three in 4th) or had never achieved an initial remission (three) at the time of transplant. Fifty-two patients received marrow from mismatched family members (haplo or DR-identical), while six received marrow from matched siblings. Most patients received myeloablative therapy consisting of total body irradiation, etoposide, cyclophosphamide, and cytosine arabinoside. Marrow from mismatched donors was T cell depleted. Only one of 52 patients transplanted with a mismatched donor survived long-term while three of six patients transplanted in relapse with a fully matched sibling donor are alive 6-10 years post BMT. The major causes of death were infection (39%) and relapse (28%). Acute GVHD grade III-IV was noted in 7% of patients. A comparable group of patients with leukemia transplanted at our center in remission using similarly mismatched family member donors (haplo or DR-identical) had an event-free survival of 28%. In conclusion, our data suggest that BMT utilizing mismatched family member donors is a poor option for patients in relapse at the time of transplant. New treatment strategies need to be developed to effectively manage these patients.